ES2288986T3 - BIOMEDICAL MOLDING. - Google Patents

Abstract

1. A biomedical molding comprising a non-biodegradable biocompatible organic polymer having radicals of the formula wherein R1 is hydroxy, C1-C4 alkyl, C1-C4 alkoxy, sulfo nitro, trifluoromethyl or halogen, m is an integer of 0 to 2, and Z is a group that functions as an activatable precursor for the formation of carbon, nitrene or benzidrol.

Description

Biomedical molded.

The present invention relates to molded, especially biomedical molded such as ophthalmic molding, comprising certain groups sensitive to radiation on its surface and to processes to join these molded to living tissue, particularly to the eyes as a prosthesis corneal

It is known, for example, from WO 95/13764, provide corneal prostheses that are composed of material porous polymer to correct the optical properties of an eye or to alter the appearance of it. Corneal inlays they are implanted in general in or on the cornea of a mammal using surgical methods, for example making an incision in the stromal tissue of the cornea to form a pocket inside from which the implant is placed, and then the incision is closed by suture medium

A more recent method involves the removal of the corneal epithelial cell layers of the cornea through scraping, placing a lenticule directly on and in intimate contact with the corneal tissue and keeping it in place during a period of time that is enough for the cells epithelials recover, grow on the implant and therefore be fixed to him permanently. The initial temporary fixation of implant on the cornea is achieved through the use of a glue biocompatible such as a commercially available glue from two components based on collagen or fibrin. But nevertheless, these glues have not yet been satisfactorily provided mainly due to severe driving problems. For example, him  surgeon always has to mix the glue components before using it Once the premix has taken place, it you only have limited periods of time to use the glue depending on the specific curing time thereof; This exerts a time-related pressure on the surgeon.  After joining the implant on the cornea, the excess glue carefully as otherwise Cured glue residue can inhibit overgrowth of the epithelial cells on the implant. Other disadvantages of known glues refer, for example, to a insufficient mechanical stability and duration. In view of this and of other disadvantages, there is a need for methods and materials improved for a temporary fixation of a polymeric implant on a cornea

Surprisingly, it has now been found that biomedical molding, particularly ophthalmic molding such as corneal implants, can be conveniently attached to a living tissue if they contain certain groups sensitive to radiation covalently attached to its surface.

The present invention is related to both in one aspect with a biomedical molding that contains a biocompatible non-biodegradable organic polymer that has attached to its surface, formula radicals

one

where R_ {1} is, for example, hydroxy, C 1 -C 4 alkyl, alkoxy C 1 -C 4, sulfo, nitro, trifluoromethyl or halogen such as, for example, fluorine or chlorine, m is an integer from 0 to 2, and Z is a group that functions as an activatable precursor for the formation of carbine, nitrene or benzidrol.

Examples of biocompatible organic polymers suitable to which the radicals of formula (1) are attached there are polyaddition and polycondensation polymers, for eg polyurethanes, epoxy resins, polyethers, polyesters, polyamides or polyimides; polyolefins, for example polyacrylates, polymethacrylates, polystyrene, polyethylene or halogenated derivatives thereof, polyvinyl acetate or polyacrylonitrile; or elastomers, for example silicones, polybutadiene or polyisoprene

A preferred group of organic polymers are those that are conventionally used for manufacturing of biomedical devices, for example ophthalmic devices such as contact lenses, artificial cornea of lenses intraocular, which are not hydrophilic by themselves. Such Materials are known by specialized personnel and can comprise, for example, polysiloxanes, perfluoroalkyl polyethers, fluorinated poly (meth) acrylates or fluorinated polymers equivalents derived for example from other carboxylic acids polymerizable, polyalkyl (meth) acrylates or polymers equivalent alkyl esters derived from other carboxylic acids polymerizable, polyolefins, or fluorinated polyolefins, such as polyvinylidene fluoride, fluorinated ethylene propylene, or tetrafluoroethylene, preferably in combination with dioxoles specific, such as perfluoro-2,2-dimethyl-1,3-dioxol.  Examples of suitable bulk materials are for example Lotrafilcon A, Neofocon, Pasifocon, Telefocon, Silafocon, Fluorsilfocon, Paflufocon, Silafocon, Elastofilcon, Fluorofocon or Teflon AF materials, such as Teflon AF 1600 or Teflon AF 2400 which are copolymers of about 63 to 73% mol of perfluoro-2,2-dimethyl-1,3-dioxol  and about 37 to 27% mol of tetrafluoroethylene, or of approximately 80 to 90% mol of perfluoro-2,2-dimethyl-1,3-dioxol  and about 20 to 10% mol of tetrafluoroethylene. A group of Particularly preferred hydrophobic polymers are homo or non-porous or particularly porous perfluoroalkyl polyether copolymers porous (PFPE) or perfluoroalkyl acrylates or methacrylates, by example those such as those disclosed in PCT WO applications 96/31546, WO 96/31548, WO 97/35906 or WO 00/15686.

Another preferred group of organic polymers Biocompatibles are those that are conventionally used for the manufacture of biomedical devices, for example lenses of contact, which are hydrophilic in themselves, since the groups hydrophilic, for example, carboxyl, carbamoyl, sulfate, sulphonate, phosphate, amine, ammonium or hydroxyl groups, are present inherently in the material. Such materials are known by specialized personnel and includes, for example, polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate (HEMA), polyvinyl pyrrolidone (PVP), polyacrylic acid, acid polymethacrylic, polyacrylamide, poly-N, N-dimethylacrylamide (DMA), polyvinyl alcohol, copolymers for example of two or more monomers from the hydroxyethyl acrylate, hydroxyethyl methacrylate group, N-vinyl pyrrolidone, acrylic acid, acid methacrylic, acrylamide, N, N-dimethylacrylamide, vinyl alcohol, vinyl acetate and the like, polyalkylene glycols such as polyethylene glycols, polypropylene glycols or copolymers in polyethylene / polypropylene glycol block. Typical examples are for example, Polimacon, Tefilcon, Methafilcon, Deltafilcon, Bufilcon, Phemfilcon, Ocufilcon, Focofilcon, Etafilcon, Hefilcon, Vifilcon, Tetrafilcon, Profilecon, Droxifilcon, Dimefilcon, Isofilcon, Mafilcon, Nelfilcon or Atlafilcon.

Another group of preferred organic polymers are amphiphilic segmented copolymers containing at least one hydrophobic segment and at least one hydrophilic segment that bind through a direct link or a member that serves as a bridge. Examples are silicone hydrogels, for example those disclosed in PCT applications WO 96/31792 and WO 97/49740.

The shape of the organic polymer may vary. within wide limits. Examples are the molding of all classes, for example tubes, films, membranes and in particular ophthalmic molding, such as contact lenses, lenses intraocular or an artificial cornea. Other examples of molding they are useful materials such as bandages for healing of wounds, bandages for the eyes, materials for release held of an active compound such as a patch for the supply of a drug, molded that can be used in surgery, such as heart valves, vascular grafts, catheters, artificial organs, encapsulated biological implants, for example, pancreatic islets, prosthetic materials such as bone substitutes, or diagnostic molds, membranes or biomedical instruments or devices.

Z in formula (1) is, for example, a group of formula

         \ vskip1.000000 \ baselineskip
      

2

         \ vskip1.000000 \ baselineskip
      

in where

R 3 is a substituent that removes electrons, for example, C 1 -C 6 fluorinated alkyl, such as a radical -C 2 F 5 or preferably a radical -CF_ {3}, R_ {1} 'independently has the meaning of R_ {1}, and m1 independently has the meaning of m.

R_ {1} and R_ {1} 'are independently one of the another preferably C 1 -C 4 alkoxy, alkyl C 1 -C 4 or sulfo.

The variable m is 1 or preferably 0. The variable m1 is preferably 0.

A group of suitable radicals of formula (1) are those where Z is a group

         \ vskip1.000000 \ baselineskip
      

3

         \ vskip1.000000 \ baselineskip
      

and m is 0.

An additional group of suitable radicals of formula (1) are those where Z is a group -N3, and m is 1 or preferably 0.

The radicals of formula (1) can be attached to the molding surface by means of any known group of binding that is biomedically acceptable and especially ophthalmically acceptable. For example, the radicals of formula (1) can be attached directly to the molding surface by means of a functional group, for example by means of a functional group of formula

-C (O) -X-

(3rd)

or

X_ {1} -C (O) -

(3b);

or

-X_ {1} -C (O) -X-

(3c);

or

-X_ {1} -C (S) -X-

(3d);

where X and X_ {1} are independently of each other a group -O- or -NR_ {2} -, where R 2 is hydrogen or C 1 -C 4 alkyl. X and X1 are each independently preferably a group -O- or -NH- and in particular each one a group -NH-.

A preferred direct link group between the radical of formula (1) and the molding surface is of formula (3a), (3b) or (3c). It must be understood in each case that in the radicals of the formulas (3a) - (3d) the left link is directed to the radical of formula (1), and the left link is directed to the organic polymer surface.

A preferred embodiment of the invention will be relates therefore to a biomedical molding that has attached to its surface, formula radicals

4

where R_ {1}, m and Z are as defined above, and A is a radical of the formulas (3a), (3b), (3c) or (3d) above. Preferably, Z is a group of formula

5

m is 0, and A is a radical of formula (3a) above. In another preferred embodiment, Z is a group -N3, m is 1 or preferably 0 and A is a radical of formula (3b) or (3d), in particular (3b).

The biomedical moldings that have joined their radical surfaces of formula (1 a) can be prepared, by example, by means of the reaction of a compound of formula

6

where A * is a radical -X1H, -NCO-, -NCS, -COOH or a carboxyl derivative, for example an acid halide, an optionally activated ester, or a anhydride, and R_ {1}, Z, X_ {1} and m are as defined previously,

with a belt group on the surface of the molded, which can be, for example, a radical -XH, -NCO, -NCS, -COOH or a carboxyl derivative, for example an acid halide, ester or anhydride.

For example, the reactions of a compound of formula (1 ') having a carboxyl group, a halide group of carboxylic acid, preferably an activated ester group, acid, lactone, isocyanate or isothiocyanate anhydride with a amino or hydroxyl compound of the molding surface, or vice versa, they are well known in the state of the art and can carry out as described in the organic chemistry textbooks. For example, the reaction of an isocyanate derivative or of isothiocyanate of formula (1 ') with an amino or hydroxyl compound of The molding surface can be carried out in a solvent inert organic such as an optionally halogenated hydrocarbon, for example petroleum ether, methylcyclohexane, toluene, chloroform, methylene chloride and the like, or an ether, for example ether diethyl, tetrahydrofuran, dioxane, or a more polar solvent such such as DMSO, DMA, N-methylpyrrolidone or even an alcohol lower, at a temperature of 0 to 100 ° C, preferably 0 to 50 ° C and particularly preferably at room temperature, optionally in the presence of a catalyst, for example an amine tertiary such as triethylamine or tri-n-butylamine, 1,4-diazabiclioctane, or such a tin compound as dibutyltin dilaurate or tin dioctanoate. Is convenient to carry out the above reactions under a inert atmosphere, for example under an atmosphere of nitrogen or argon.

In the case of a compound of formula (1 ') or of the molding surface carrying a carboxyl anhydride group, the reaction of the carboxylic anhydride with the molding surface or of the compound of formula (1 ') carrying an amino or hydroxyl group can be carried out as described in the textbooks of organic, for example in an aprotic solvent, for example one of the aprotic solvents mentioned above, at a temperature from room temperature to about 100 ° C.

In the case of a compound of formula (1 ') or of the molding surface carrying a carboxylic group, the reaction of the carboxylic group with the molding surface or compound of formula (1 ') carrying an amino or hydroxyl group can be carried out under the conditions that are customary for formation of the ester or amide, for example in an aprotic environment at a temperature approximately from room temperature to approximately 100 ° C. It is further preferred to carry out the reaction. of esterification or amidation in the presence of an agent of activation for example N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide (EDC), N-hydroxy succinimide (NHS), sulfo-N-hydroxy succinimide or N, N'-dicyclohexyl carbodiimide (DCC) or in the presence of an o- (benzotriazole) -uronium salt such as o- (benzotriazol-1-i -) - N, N, N, N-tetramethyluronium hexafluoro phosphate. More preferably, the carboxylic acid derivative of formula (1 ') was converted prior to an activated ester using one of the agents of activation mentioned above, and the activated ester reacts then additionally with the hydroxyl groups or preferably surface amino.

The resulting modified biomedical molding they are conveniently purified before using them, for example by washing or extraction medium in a suitable solvent.

The compounds of formula (1 ') are known and partially commercially available or can be prepared from according to known processes.

Appropriate Belt Functional Groups may be present inherently (a priori) in the molding surface to be modified. If the surface of molded contains very few or no reactive group, the surface of the material could be previously modified by means of methods known, for example plasma chemical methods (see, for example, WO 94/06485), or conventional functionalization with groups such as -OH, -NH2 or -CO2H produced.

Preferably, the amino or hydroxy groups of the molding surface react with a compound of formula (1 ') having a carboxyl group, carboxylic acid anhydride, activated carboxylic acid ester, carboxylic acid halide, isocyanate or thioactive isothiocyanate. According to a preferred alternative also, the carboxyl, acid ester groups activated carboxylic or surface carboxylic acid halide react with a compound of formula (1 ') that has a group amino or hydroxy belt.

According to an additional modality of the invention, the radicals of formula (1) bind to the surface of molded by means of a spacer group. The spacer groups suitable are, for example, of formula

-A_ {1} -C (O) -X-

(3e);

or

-A_ {1} -X-C (O) -

(3e ')

or

-X 1 -C (O) -NH-R-NH-C (O) -X-

(3f);

or

-X_ {1} -C (O) -A2 -C (O) -X-

(3g);

         \ newpage
      

or

-C (O) - X_ {1} - A_ {3} - X-C (O) -

(3h);

or

-CO)- X_ {1} -A_ {4} -C (O) -X-

(3i);

or

-X_ {1} -C (O) -A_ {-5} -X-C (O) -

(3j)

in where

A_ {1} is alkylene C_ {1} -C_ {30} that may be interrupted by -O- except for C 1 alkyl;

A 2 is alkylene C_ {1} -C_ {200} that may be interrupted by -O- except for C 1 alkyl;

A 3 is alkylene C_ {2} -C_ {200} that may be interrupted by -O- or by -NH-;

A_ {4} and A_ {5} are independently each one C2-C200 alkylene which can be interrupted by -O- or -NH-;

-C (O) NH-, -NH (CO) -, -C (O) O- or -O (O) C-;

R is C 1 -C 18 alkylene linear or branched or unsubstituted or alkyl C 1 -C 4 or arylene C 6 -C 10 substituted by alkoxy C 1 -C 4, aralkylene C 7 -C 18, arylene C 6 -C 10 -alkylene C 1 -C 2 -arylene C 6 -C 10, cycloalkylene C 3 -C 8, cycloalkylene C 3 -C 8 -alkylene C 1 -C 6, cycloalkylene C 3 -C 8 -alkylene C 1 -C 2 -cycloalkylene C 3 -C 8 or alkylene C 1 -C 6 -cycloalkylene C 3 -C 8 -alkylene C 1 -C 6; and X and X_ {1} are as defined previously.

With the radicals of the formulas (3e) - (3j) you you must understand in each case that the link to the left is directed to the radical of formula (1) and the link to the right is directed to the surface of the organic polymer.

A1 is preferably a branched or preferably linear C 1 -C 12 alkylene radical or a radical - (CH 2 CH 2 O) 1-5 -
CH 2 CH 2 - and in particular a linear C 1 -C 4 alkyl or - (CH 2 CH 2 O) 1-3 -CH 2 CH_ { 2}-.

R as alkylene in formula (3f) is preferably an alkylene radical C 3 -C 14 linear or branched, plus preferably to C 4 -C 12 alkylene radical linear or branched and most preferably an alkylene radical C 6 -C 10 linear or branched.

When R is arylene, this is, for example, naphthylene or especially phenylene, each of them can be substituted, for example, by C 1 -C 4 alkyl or by C 1 -C 4 alkoxy. Preferably, R as arylene is 1,3- or 1,4-phenylene which is not substituted or substituted by alkyl C 1 -C 4 or by alkoxy C_ {1} -C_ {4} in ortho position to at least one site of binding.

R as aralkylene is preferably naphthylalkylene and most preferably phenylalkylene. The group alkylene in aralkylene preferably contains from 1 to 12, more preferably from 1 to 6 and most preferably from 1 to 4 atoms of carbon. Most preferably, the alkylene group in aralkylene is methylene or ethylene.

When R is cycloalkylene, it is preferably C 5 -C 6 cycloalkylene and most preferably cyclohexylene that is not substituted or substituted by methyl.

When R is cycloalkylene-alkylene, is preferably cyclopentylene-alkylene C_ {1} -C_ {{}} and especially cyclohexylene-alkylene C_ {C} {C4}, each unsubstituted or mono- or poly-substituted by alkyl C 1 -C 4, especially methyl. Plus preferably, the cycloalkylene-alkylene group it is cyclohexylene-ethylene and, most preferably, cyclohexylene-methylene, each unsubstituted or substituted in the cyclohexylene radical by between 1 and 3 groups methyl.

When R is alkylene-cycloalkylene-alkylene, it is preferably alkylene C 1 -C 4 -cyclopentylene-alkylene  C 1 -C 4 and especially alkylene C 1 -C 4 -cyclohexylene-alkylene C_ {C} {C4}, each unsubstituted or mono- or poly-substituted by alkyl C 1 -C 4, especially methyl. Plus preferably the group alkylene-cycloalkylene-alkylene it is ethylene-cyclohexylene-ethylene and, most preferable, is methylene-cyclohexylene-methylene, each unsubstituted or substituted in the cyclohexylene radical by between 1 and 3 methyl groups.

R as cycloalkylene C 3 -C 8 -alkylene C 1 -C 2 -cycloalkylene C 3 -C 8 or arylene C 6 -C 10 -alkylene C 1 -C 2 -arylene C 6 -C 10 is preferably cycloalkylene-methylene C 5 -C 6 -cycloalkylene C_ {5} -C_ {6} or phenylene-methylene-phenylene, each of which may be unsubstituted or substituted in the ring cycloalkyl or phenyl by one or more methyl groups.

The radical R in the formula (3f) has a symmetric structure or, preferably, a structure asymmetric

A preferred group of spacer radicals it comprises those of formula (3f), wherein R is alkylene C 6 -C 10 linear or branched; or cyclohexylene-methylene or cyclohexylene-methylene-cyclohexylene each unsubstituted or substituted in the cyclohexyl moiety by between 1 and 3 methyl groups.

The divalent radical R in the formula (3f) is preferably derived from a diisocyanate and most preferably from a diisocyanate selected from the isophorone diisocyanate (IPDI) group, 4,4'-methylenebis (cyclohexyl isocyanate), 1,6-diisocyanate-2,2,4-trimethyl-n-hexane (TMDI), Methylenebis (cyclohexyl-4-isocyanate) and hexamethylene diisocyanate (HMDI).

A2 in the formula (3g) is preferably linear or branched C 1 -C 24 alkylene or C4-C16 alkylene which is interrupted by -O-, more preferably C 1 -C 6 alkylene or C 8 -C 60 alkyl which is interrupted by -O- and most preferably C 1 -C 4 alkylene or (alq) -O- (CH 2 CH 2) 8-25 - (alq) -,  where (alq) is, for example, alkyl C 1 -C 6, preferably alkyl C 1 -C 4, more preferably alkyl C 1 -C 3 and in particular ethyl.

A 3 is preferably alkylene C 1 -C 24 linear or branched or alkylene C_ {4} -C_ {160} which is interrupted by -O- or -NH-, more preferably C 1 -C 6 alkylene or C 8 -C 60 alkyl which is interrupted by -O-, and most preferably C 1 -C 4 alkylene, or a radical - (alq) -O- (CH 2 CH 2 O) 8-25 - (alq) -,  where (alq) is as defined above.

A4 as alkylene is, for example, C 2 -C 24 alkylene branched or preferably linear, more preferably alkylene C 2 -C 18 and in particular alkylene C_ {4} -C_ {12}. An alkylene radical A 4 which is interrupted by -O- is, for example, a radical - (CH 2 CHR 5 O) x - (alq) -, where (alq) is as defined above, R 5 is hydrogen or methyl and x is about 2 to about 99. A radical preferred alkylene A 4 which is interrupted by -O- is a radical - (CH 2 CH 2 O) x - (CH 2 CH 2) -, in where x is from 4 to 80 and in particular from 8 to 80. An alkylene radical A_ {4} which is interrupted by -C (O) NH- is, by example, a polypeptide radical of formula - (CHR 6 -C (O) NH) t -CHR 6 -, wherein R 6 is hydrogen or alkyl C_ {1} -C_ {4} which is unsubstituted or substituted by hydroxy, carboxy, carbamoyl, amino, phenyl, o-, m- or p-hydroxyphenyl, imidazolyl, indolyl or a radical -NH-C (= NH) -NH2 and t is an integer from about 2 to 80. An alkylene radical A 4 which is interrupted by -C (O) O- or -OC (O) - is, for example, a polyester radical. A preferred radical of formula (3i) corresponds to the formula -C (O) O- (CH 2 CH 2 O) 8-80 -CH 2 CH 2 C (O) NH-  or -C (O) O- (alq ') - C (O) NH- where (alq ') is C 2 -C 18 alkylene branched or preferably linear.

A5 as alkylene is, for example, C 2 -C 24 alkylene branched or preferably linear, more preferably alkylene C 2 -C 18 and in particular alkylene C_ {4} -C_ {12}. An A 5 alkylene radical that is interrupted by -O- is, for example, a radical - (alq) - (OCHR 4 CH 2) x -, where (alq) is as defined above, R 4 is hydrogen or methyl and x is about 2 to about 99. A radical preferred alkylene A 5 which is interrupted by -O- is a radical - (CH 2 CH 2) - (OCH 2 CH 2) x -, in where x is from 4 to 80 and in particular from 8 to 80. An alkylene radical A_ {5} which is interrupted by -NHC (O) - is, for example, a polypeptide radical of formula -CHR 5 - (NHC (O) -CHR 5) t -, wherein R 5 is hydrogen or alkyl C_ {C} {C4} which is unsubstituted or substituted by hydroxy, carboxy, carbamoyl, amino, phenyl, o-, m- or p-hydroxyphenyl, imidazolyl, indolyl or a radical -NH-C (= NH) -NH2 and t is a integer from about 2 to 80. An alkylene radical A_ {5} which is interrupted by -C (O) O- u -OC (O) - is, for example, a polyester radical.

An additional preferred embodiment of the invention is therefore related to a biomedical molding that contains attached to its surface, radicals of the formula

         \ vskip1.000000 \ baselineskip
      

7

         \ vskip1.000000 \ baselineskip
      

where for each one between R_ {1}, m and Z apply the meanings and preferences given above, and A 'is a radical of the formula (3e), (3e'), (3f), (3g), (3h), (3i) or (3j) above and preferably a radical of formula (3f), (3g) or (3i), where for the variables contained there, the meanings and preferences mentioned apply previously.

The biomedical moldings that have attached to its radical surface of formula (1 b) wherein A 'is a radical of the above formula (3e) can be prepared, for example, by reaction of a compound of formula

         \ vskip1.000000 \ baselineskip
      

8

where A_ {1}, R_ {{}}, Z and m are as defined above, or a carboxylic derivative of the same, for example a halide, ester or anhydride thereof, with -XH groups of the molding surface, where X is as it is defined above. The moldings that have attached to their radical surfaces of formula (1 b) wherein A * is a radical of formula (3e ') above, can be prepared, for example, by reaction of a compound of formula (1 ') above, wherein A * is a radical -X1H, with carboxyl groups or a derivative of the themselves from the surface of molded

The biomedical molding that they have attached to their radical surface of formula (1 b) wherein A 'is a radical of the formula (3f) or (3g) above, can be prepared, for example, by means of the reaction of a compound of the formula (1 ') above, where A * are radical groups -X_ {1} H and -XH of the molding surface, where X and X_ {1} are as defined above, in any order with a compound of formula ONC-R-NCO where R is as it is defined above, or with a compound of formula HOOC-A 3 -COOH or a derivative carboxylic thereof mentioned above, wherein A 3 is as defined above.

The biomedical molding that they have attached to their radical surface of formula (1 b) wherein A 'is a radical of the formula (3h) above, can be prepared for example, by means of the reaction of a compound of the formula (1 ') above, in where A * is a -COOH radical or a carboxylic derivative thereof mentioned above, and the -COOH groups or a derivative carboxylic thereof mentioned above from the surface of the molded, in any order with a compound of formula X_ {1} H-A_ {-3} -XH where X and X_ {1} are as defined above.

The biomedical molding that they have attached to their radical surface of formula (1 b) wherein A 'is a radical of the formula (3i) above, can be prepared for example, by means of the reaction of a compound of the formula (1 ') above, in where A * is a -COOH radical or a carboxylic derivative thereof mentioned above, and the -COOH groups or a derivative carboxylic thereof mentioned above, and the -XH groups of the molding surface, in any order with a compound of formula HX 1 -A 4 -COOH or a carboxylic derivative thereof as mentioned above, in where A_ {4}, X and X_ {1} are as defined above.

The biomedical molding that they have attached to their radical surface of formula (1 b) wherein A 'is a radical of the formula (3i) above, can be prepared for example, by means of the reaction of a compound of the formula (1 ') above, in where A * is a radical -X1H and -COOH groups or a derivative carboxylic thereof mentioned above from the surface of the molded, in any order with a compound of formula HOOC-A_ {5} -XH where A_ {5}, X and X_ {1} are as defined above.

The compounds of formula (1 ') and (1' ') as well as the compounds of the formulas ONC-R-NCO, HOOCA_ -COOH, X 1 H-A 3 -XH, HX 1 -A 4 -COOH and HOOC-A5 -XH are well known in art and are commercially available in part. In addition, the reactions between reactive groups of the molding surface, a suitable compound of formula (1 ') or (1' ') and optionally one of the aforementioned bifunctional compounds for produce a molded surface that contains radicals from the formula (1b) can be carried out in each case under conditions which are common for the formation of ester, amide, urethane or urea, for example as described above.

Throughout the entire application, such terms as carboxy, carboxylic acid, -COOH, sulfo, amino, -NH2 and similar always include free acid or amine as well as a suitable salt thereof, for example a biomedically salt or in particular ocularly acceptable thereof such as, by example, a sodium, potassium, ammonium or similar salt (of a acid), or an acid halide such as a hydrochloride (of a amine).

According to yet another embodiment of the invention, the radiation sensitive radicals of formula (1) can be join the biomedical molding through a process that includes the stages of (i) providing the molding surface with groups reagents by means of plasma-induced polymerization of a ethylenically unsaturated compound carrying a reactive group; Y (ii) react the reactive surface groups modified molding with a belt compound that contains a radical of formula (1). A suitable process is described for the plasma-induced polymerization of functional monomers, by example, in WO 98/28026. The suitable functional monomers that can be used at this stage are any of the compounds polymerizable unsaturated bearing reactive groups and can be evaporated and introduced into the plasma generating apparatus to make contact with the material to be coated supplied there. Examples of reactive groups that are contemplated here include isocyanate (-NCO), isothiocyanate (-NCS), epoxy, anhydride, azlactone and lactone (for example, lactone?, γ, δ). A suitable vinyl monomer that has a reactive group in this context is, for example, a compound of formula

         \ vskip1.000000 \ baselineskip
      

9

10

         \ vskip1.000000 \ baselineskip
      

eleven

         \ vskip1.000000 \ baselineskip
      

12

         \ vskip1.000000 \ baselineskip
      

13

in where

R 6 is hydrogen, alkyl C 1 -C 6 or unsubstituted phenyl or hydroxy substituted,

R 7 is hydrogen, alkyl C 1 -C 4 or halogen,

R_ {8} and R_ {8} 'are each a radical ethylenically unsaturated having 2 to 6 carbon atoms, or R_ {8} and R_ {8} 'together form a bivalent radical -C (R_ {7}) = C (R_ {7}) - where R_ {7} is as defined above and R_ {7} 'independently has the meaning of R_ {7}, and (Alq *) is alkylene C 1 -C 6, and (Alk **) is alkylene C_ {2} -C_ {12}.

The following preferences apply to variables contained in formulas (4a) - (4e):

R 6 is preferably hydrogen or C 1 -C 4 hydroxyalkyl, in particular hydrogen or β-hydroxyethyl.

R 7 is preferably hydrogen or methyl.

R 8 and R 8 'are preferably each vinyl or 1-methylvinyl, or R 8 and R 8 'form together a radical -C (R_ {7}) = C (R_ {7} ') - in where

R 7 and R 7 are independently each one hydrogen or methyl.

(Alq *) is preferably methylene, ethylene or 1,1-dimethylmethylene, in particular a radical -CH 2 - or -C (CH 3) 2 -.

(Alk **) is preferably alkylene C_ {2} -C_ {4} and in particular 1,2-ethylene.

Vinyl monomers particularly Preferred having a reactive group are 2-Isocyanatoethylmethacrylate (EMI), 2-vinyl azlactone, 2-vinyl-4,4-dimethyl-azlactone, Acrylic acid, methacrylic acid, acrylic anhydride, anhydride meleic acid, 2-hydroxyethyl acrylate (HEA), 2-hydroxymethacrylate (HEMA), glycidyl acrylate or glycidyl methacrylate.

The appropriate belt compounds in the step (ii) containing a radical of formula (1) are, for example,  of the formula (1 ') above, where A * is, for example, -X1H, -COOH or a carboxylic derivative, for example a halide acid, ester or anhydride thereof, and R1, Z and m are as defined above.

Biomedical molding according to the invention containing radicals of the formula (1) are sensitive to radiation, this means that by irradiation, for example with UV or visible light, the molding surface has carbine highly reactive, nitrene or benzidrol radicals that can react with all kinds of organic material, including synthetic and natural polymers with bond formation covalent -C-C- or -C-N-C-. Therefore, the moldings Biomedicals of the invention can be chemically bonded virtually on each organic material including living tissue that converts them in a valuable tool for surgery, particularly for ophthalmic surgery

Therefore it is a particular objective of the invention providing a corneal implant, which comprises joining its radical surface of the formula (1). Said implant may be composed of any of the synthetic materials known with the requirement of mechanical properties, as mentioned previously. The corneal implant is adapted for recolonization epithelial, which means, that the polymeric material starting from which the implant is formed does not inhibit cell binding or motility. The radicals of formula (1) bind to the material synthetic forming the implant as described above. From according to one embodiment of the invention, only part of the implant, preferably only the internal anterior surface,  It is supplied with radicals of formula (1) for the purpose of fix it on the cornea. According to another modality, both the posterior surface as anterior exterior of the implant with Radiation sensitive radicals can be used to modify additionally the surface the outer surface of the implant, for example with the purpose of facilitating a cellular union such as described here.

The fixation of a corneal implant according to the present invention on the cornea can be initiated, by for example, by irradiation, particularly by irradiation with UV or visible light Preferably, the cornea is previously prepared for the attachment of the implant, for example by removing the layers of scraped corneal epithelial cells. In general, it is placed the implant in intimate contact with the corneal tissue and then irradiated The light sources suitable for irradiation are known by the operator and include for example lamps mercury, high pressure mercury lamps, xenon lamps, carbon arc or sunlight lamps. They can be used Sensitizers to change the wavelength of irradiation.  In addition, a suitable filter can be used to limit the irradiation at a specific range of wavelength. Preferably, the surface of the implant to which it has been previously applied the compound (s) that contains radicals of formula (1) is irradiated with light of a length wave ≥300 nm, preferably between 350 and 400 nm. He irradiation time period is not critical but is usually in the range up to 30 minutes, preferably from 10 seconds up to 10 minutes, and more preferably from 15 seconds to 5 minutes, and particularly preferably from 20 seconds to 1 minute.

A preferred method of placing an implant corneal on a cornea then comprises

(i)

provide an implant that contains groups of formula (1) on its anterior surface only;

(ii)

place the implant in contact with corneal tissue; Y

(iii)

irradiate the implant thereby fix the implant on the cornea.

After anterior implant fixation over the cornea, the posterior surface of the implant can be coat with a compound that promotes tissue growth as described here above.

Another preferred method of placing an implant corneal on a cornea comprises

(i)

provide an implant that contains groups of formula (1) on both its posterior surface and previous,

(ii)

place the implant in contact with corneal tissue,

(iii)

before or after stage (ii) coat the back surface with one or more components that promote tissue growth adjacent to the implant placed, Y

(iv)

irradiate the implant with which this it is fixed on the cornea, and the compound that promotes growth of the tissue is fixed on the back surface of the implant.

Suitable compounds that promote tissue growth in both methods mentioned above they are, for example, albumin, an extracellular matrix (ECM), fibronectin, laminin, chondroitano sulfate, collagen, proteins for cell binding, antigelatin factor, globulin insoluble in cold, condronectin, epidermis growth factor, protein mussel adhesive, sialo-proteins, thromboespondin, vitronectin, and different proteoglycans, and / or derivatives of the above or mixtures thereof. The compounds Preferred that promote tissue growth are collagen, proteins for cell binding or growth factor of the epidermis.

The biomedical moldings of the invention provide a new route for the placement of a corneal implant on a cornea that is easy to perform, does not affect the vision of the wearer and is safe. In particular, a stable mechanical fixation of the implant on the cornea is obtained so that it lasts for a sufficient period of time for the epithelial cells to recover, grow on the implant and therefore fix it permanently. The implants are very easy to handle, since the use thereof does not involve, for example, a premixing of the glue components or a prolonged pressure by the surgeon due to the specific cure times of the glue components. In addition, a tedious removal of excess glue is not necessary after fixing the implant on the cornea, and the above problem of inhibiting excessive growth due to glue residues does not exist. In addition, the implants of the invention can be conveniently stored for a long period of time, for example in the form of a plate covering the protective sheets of the (s)
surface (s). The implant is then immediately ready for use, simply by removing the sheet (s) that cover the surface (s). All the advantages mentioned above apply naturally not only to contact lenses but also to other biomedical moldings according to the invention as mentioned above.

In the examples, if not indicated otherwise, the quantities are expressed by weight, temperatures are expressed in Celsius degrees.

Example 1 Synthesis of a diazirine NHS ester

They are placed on a round bottom ball of 500 mL 7.06 g (36.81 mmol) of hydrochloride N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide  together with 200 mL of water at pH 12. After 15 minutes of stirring at room temperature 50 mL of dichloromethane are added. The extraction is repeated three times with 50 mL of dichloromethane. Be combine the organic phases, dry them over MgSO4, dry Filter and dry in vacuo. The free base is placed on a ball of 250 mL round bottom and dissolved in 150 mL of acetonitrile (28.4 ppm water). 17.19 g (1212 mmol Cl) of polymer are added  Merrifield The suspension is heated at 100 ° C at reflux for 16 hours. After cooling to room temperature it was washed 3 times the Merrifield polymer activated with 50 mL of acetonitrile, 2 times with 50 mL of diethyl ether and dried under high vacuum.

Amber round bottom ball of 100 mL, 300 mg (1.30 mmol) of acid 4- (1-azi-2,2,2-trifluoroethyl) benzoic acid,  135 mg (1.17 mmol) of N-hydroxysuccinimide, 6.3 g of activated Merrifield polymer and 45 mL of chloroform and stirred at room temperature. DC control indicates complete conversion after 30 minutes The mixture is filtered and washed with chloroform. The filtrate is dried under high vacuum. The complete reaction is determined by means of 1 H NMR spectroscopy.

         \ vskip1.000000 \ baselineskip
      

Example 2 Amino functionalization of the lenticles using plasma from 1,2-Diaminocyclohexane (DACH)

Lenticles composed of a material of perfluoroalkyl polyether (for synthesis see WO 00/15686, Example 2) are placed, after extraction in isopropanol, toluene and again in isopropanol, on the glass support inside the plasma reactor equipped with an external ring electrode and a 27.13 MHz radio frequency (RF) generator for generation of a discharge plasma that emits cold light, inductively coupled. The distance between the substrates and the lower bore of the Plasma zone is 12 cm. The reactor is evacuated at a pressure of 0.008 mbar, and these conditions are maintained for one hour. Then, the argon plasma gas flow rate is programmed within the plasma zone of the reactor at 20 sccm (centimeter standard cubic), the pressure in the reactor is adjusted to 0.12 mbar and The RF generator is turned on. Plasma discharge is maintained of a power of 250 watts for a total time of 1 min (with the purpose of cleaning and activating the lens surfaces). Then, the 1,2-DACH steam is introduced into the reactor chamber from the DACH tank (maintained at 24 ° C) at a pressure of 0.15 mbar for 1 min. After this, it they chose the following parameters for polymerization by DACH plasma: Argon flow rate for excitation of plasma = 5 sccm, argon transport gas flow rate for DACH transport = 5 sccm, unit temperature DACH evaporation = 24 ° C, the distance between the lower edge of the plasma zone and the substrates = 5 cm, pressure = 0.2 mbar, and plasma power = 100 W. Lenticles are treated about 5 minutes with a pulsating plasma d download of cold light (1 \ museg on, 3 \ museg off). After 5 minutes of deposition the plasma discharge is interrupted and you allows DACH steam to flow into the reactor for another 5 min. The reactor is then evacuated and held for 30 min at a pressure of 0.008 mbar for the purpose of removing monomer residual and activated species. The internal pressure is brought to atmospheric pressure through the use of dry nitrogen.

A portion of the lenticles that had been treated on the internal anterior surface is discharged from the reactor. Another portion of lenticles is held in the reactor, turned and the entire procedure is repeated to coat the other side of the substrates.

         \ newpage
      

Example 3 Binding of a photoreactive diazirine on lenticles without spacer

9.25 mg of the NHS ester of diazirine of Example 1 in 12 mL of isopropanol. 8 lenticles of Example 2 having DACH plasma on one side (amino density 12 / nm2) are installed between two metal grilles, added to the solution and shake moderately for 72 hours at temperature ambient. The lenticles are extracted 4 times with 12 mL of Isopropanol and equilibrate in stages with water.

Example 4 Binding of photoreactive diazirine on lenticles through of a hydrophilic spacer

The NHS ester of a polyethylene glycol bifunctional (PEG) formula

HOOC- (CH 2 CH 2 O) x -CH 2 CH 2 -FMOC

where FMOC is 9-fluorenylmethylcarbamate and the average of x is approximately 75 to 80 (molecular weight 3400 Da, Shearwater) are prepared according to a method as described in Example 1. It is dissolve 84.3 mg of the ester of FMOC-PEG-NHS (28 µmol), in 7 mL of acetonitrile. 7 lenticles of Example 2 (plasma of DACH on one side, amino density 12 / nm 2) and stirred overnight at room temperature. 10 times are removed contact lenses with 7 mL of acetonitrile. The solvent is removed and add 7 ml of 20% piperidine in acetonitrile and stir for 30 min. An extraction with 7 mL of acetonitrile 7 is carried out times. The solvent is changed to isopropanol. 19.8 mg dissolve of Example A in 7 mL of isopropanol and added to the lenticles and Stir at room temperature overnight. The Lenticles 7 times with 7 mL of isopropanol. After extraction the lenticules are balanced with Water.

Example 5 Linking a photoreactive diazirine on lenticles to through a hydrophobic spacer

1 g of undechanoic amino acid (4.9 mmol) and 100 mL of water. 6 mL of 1 N HCl is added to the suspension (6 mmol). The clear solution is freeze dried. Is transfered an acid group of undechanoic acid hydrochloride to the ester NHS active using the method of Example 1. 60 mg are dissolved of the NHS ester undecanolic amino hydrochloride in 3 mL of acetonitrile 3 mL of isopropanol are added. 7 lenticles added of Example 2 (DACH plasma on one side, amino density of 12 / nm2) and stir for 72 hours. The lenticles are removed with isopropanol and acetonitrile. 6 drops of triethylamine are added and stir for 4 hours. The lenticles are extracted 5 times with 7 mL of acetonitrile The solution is changed to isopropanol. After the addition of 20.1 mg of the compound of Example 1 is stirred all overnight. The lenticles are then extracted 6 times with 7 mL of isopropanol and finally equilibrated with water.

Example 6 Analysis of the adhesive strength on an eye sample of pork

The epithelium of fresh pig eyes is removed. The photoreactive lenticles of Examples 3, 4 and 5 are placed in an aqueous solution and water is removed from the surface of the contact lenses using a cleaning cloth. The lenticules are placed over pig eyes by gentle pressure. Used a blue light source (EFOS lamp) for irradiation. After irradiation for 120 seconds some droplets of Water over the lenticles. The glue analysis is carried out by means of three methods: finger thrust analysis, analysis peeling and stability analysis by placing the lenticles with the glue with the pig's eye in saline solution for several days. All samples are compared to those that did not receive irradiation. High adhesion properties are found for the Example 3 and very high for Example 5. Properties are found highly adhesive for Example 4.

Example 7 Analysis of the glue on an eye of live cats

The cat's eye epithelium is removed and place the lens of Example 3 over the eye as described in Example 6. After irradiation for 120 seconds using a blue light lamp observes the cat for the stability of the glue. The lenticule remains in the cat's eye for 2 days, and healthy-looking epithelial cells have come out over the implant flange and have begun to cover it. After stirring the lenticule, the cells grew over the wound completely.

         \ vskip1.000000 \ baselineskip
      

References cited in the description

This list of references cited by the Applicant is solely for the convenience of the reader. No way part of the European patent document. Although it has had great Be careful when collecting, you cannot exclude errors or omissions and the EPO rejects all responsibility in this regard.

Patent documents cited in the description

WO 9513764 A [0002]

WO 9631792 A [0009]

WO 9631546 A [0007]

WO 9749740 A [0009]

WO 9631548 A [0007]

WO 9406485 A [0025]

WO 9735906 A [0007]

WO 9828026 A [0052]

WO 0015686 A [0007] [0066]

Claims (13)

1. A biomedical molding comprising a biocompatible non-biodegradable organic polymer that has attached to its radical surface of formula

           \ vskip1.000000 \ baselineskip
        

14 where R 1 is hydroxy, C 1 -C 4 alkyl, alkoxy C 1 -C 4, sulfo nitro, trifluoromethyl or halogen, m is an integer from 0 to 2, and Z is a group that functions as an activatable precursor for the formation of carbine, nitrene or benzidrol. 2. A biomedical molding according to the claim 1, wherein the biocompatible organic polymer is Select polyurethane, epoxy resin, polyether, polyester, polyamide, polyimide, polyolefin, polybutadiene, polyisoprene and a silicone. 3. A biomedical molding according to the claim 1 or 2, wherein the biocompatible organic polymer is select from a polysiloxane, perfluoroalkyl polyether, fluorinated poly (meth) acrylate, polyalkyl (meth) acrylate, polyolefin and a polyolefin fluoridated 4. A biomedical molding according to anyone of claims 1 to 3, wherein Z in formula (1) is a formula group

           \ vskip1.000000 \ baselineskip
        

fifteen where R 3 is alkyl C 1 -C 6 fluorinated, R 1 'is hydroxy, C 1 -C 4 alkyl, alkoxy C 1 -C 4, sulfo, nitro, trifluoromethyl or halogen, and m1 is 0 or one. 5. A biomedical molding according to anyone of claims 1 to 4, which contains attached to its surface formula radicals

           \ vskip1.000000 \ baselineskip
        

16 where R_ {1}, m and Z are as defined in claim 1, and A is a functional group of formula

-C (O) -X-

(3rd)

or

X_ {1} -C (O) -

(3b);

or

-X_ {1} -C (O) -X-

(3c);

or

-X_ {1} -C (S) -X-

(3d);

where X and X_ {1} are independently of each other a group -O- or -NR2 -, and R2 it's hydrogen or alkyl C_ {1} -C_ {4}. 6. A biomedical molding according to anyone of claims 1 to 4, which contains attached to its surface formula radicals 17 where R_ {1}, m and Z are each one as defined in claim 1, and A 'is a group spacer formula

-A_ {1} -C (O) -X-

(3e);

or

-A_ {1} -X-C (O) -

(3e ')

or

-X 1 -C (O) -NH-R-NH-C (O) -X-

(3f);

or

-X_ {1} -C (O) -A2 -C (O) -X-

(3g);

or

-C (O) - X_ {1} - A_ {3} - X-C (O) -

(3h);

or

-CO)- X_ {1} -A_ {4} -C (O) -X-

(3i);

or

-X_ {1} -C (O) -A_ {-5} -X-C (O) -

(3j)

in where A_ {1} is alkylene C_ {1} -C_ {30} that may be interrupted by -OR-; A 2 is alkylene C_ {1} -C_ {200} that may be interrupted by -O- except for C 1 alkyl; A 3 is alkylene C_ {2} -C_ {200} that may be interrupted by -O- or by -NH-; A_ {4} and A_ {5} are independently each one C2-C200 alkylene which may be interrupted by -O- or -NH-, -C (O) NH-, -NH (CO) -, -C (O) O- or -O (O) C-; R is C 1 -C 18 alkylene linear or branched or unsubstituted or alkyl C 1 -C 4 or arylene C 6 -C 10 substituted by alkoxy C 1 -C 4, aralkylene C 7 -C 18, arylene C 8 -C 10 -alkylene C 1 -C 2 -arylene C 8 -C 10, cycloalkylene C 3 -C 8, cycloalkylene C 3 -C 8 -alkylene C 1 -C 6, cycloalkylene C 3 -C 8 -alkylene C 1 -C 2 -cycloalkylene C 3 -C 8 or alkylene C 1 -C 6 -cycloalkylene C 3 -C 8 -alkylene C 1 -C 6; X and X_ {1} are each independently of the other a group -O- or -NR2 -, and R2 is hydrogen or C 1 -C 4 alkyl. 7. A biomedical molding according to anyone of claims 1 to 4, wherein the radicals of formula (1) they are attached to the molding surface by means of a process which comprises the stages of

(i)

provide the molding surface with reactive groups by means of plasma induced polymerization of an ethylenically unsaturated compound that carries a reactive group, Y

(ii)

react reactive groups of the modified molding surface with a belt compound which contains a radical of formula (1).

8. A biomedical molding according to anyone of claims 1 to 7, which is an ophthalmic molding, in particular a corneal implant. 9. The use of biomedical molding according to any of the preceding claims for manufacturing of a corneal implant containing groups of formula (1) according to claim 1 only on a part of the implant in a corneal implant placement process on a cornea that understand the stages of

(i)

put the implant in contact with the corneal tissue; Y

(ii)

irradiate the implant with which this It is fixed on the cornea.

10. The use of biomedical molding according to claim 9 wherein the part of the implant having groups of formula (1) according to claim 1 is the surface previous internal only. 11. The use of a biomedical molding according to any one of claims 1 to 8 for the manufacture of a corneal implant containing groups of formula (1) according to the claim 1 on both its posterior and anterior surface, in a process of placing a corneal implant on a cornea that understand the stages of

(i)

place the implant in contact with the corneal tissue,

(ii)

before or after stage (i) coat the back surface with one or more components that promote tissue growth adjacent to the implant placed; and

(iii)

radiate the implant thereby this one is fixed on the cornea, and the compound that promotes the tissue growth is fixed on the posterior surface of the implant.

12. A use according to claim 10, in where the compound that promotes tissue growth is a albumin, an extracellular matrix (ECM), fibronectin, laminin, chondroitano sulfate, collagen, proteins for cell binding, antigelatin factor, cold insoluble globulin, condronectin, epidermis growth factor, adhesive protein of mussel, sialo-proteins, thrombospondin, vitronectin, proteoglycan, or a mixture of two or more of the mentioned compounds. 13. The use of a biocompatible organic polymer non-biodegradable which comprises the binding to its surface of radicals of formula 18 where R_ {1} is a substituent that removes electrons, m is an integer from 0 to 2, and Z is a group that works as an activatable precursor for the formation of carbine, nitrene or benzidrol, for the manufacture of intraocular lenses to be implanted inside or on a cornea.